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N Haran-Ghera

Publications and source records attributed to N Haran-Ghera.

At least 19 recordsLinked to original sources
PubMed1992

Termination of the B cell lymphoma dormant state in thymectomized AKR mice.

AKR mice are highly susceptible to spontaneous T cell lymphomagenesis and thymus removal at the age of 1 to 3 mo greatly reduces its development. Twelve-mo-old AKR mice thymectomized at young age were shown previously to carry potential lymphoma cells that could be triggered to develop into B cell lymphomas (80 to 100%) after removal from their host "restrictive" environment into young histocompatible hosts. Additional attempts were made to terminate the potential lymphoma cell dormant state in 12-mo-old thymectomized AKR mice. Replenishment of some deficiencies caused by thymectomy at a young age, including a s.c. syngeneic thymus graft or a single injection of the dual tropic recombinant virus isolates DTV-71 or MCF-247 into 12-mo-old thymectomized AKR mice resulted in Ly-1+ pre-B or B cell lymphoma development in 80 to 98% of these treated mice. In vivo elimination of T cell subsets by administration of cyclosporin A or by mAb expressed on Th cells (anti-CD4) or cytotoxic T cells (anti-CD8) stimulated the progression of dormant potential lymphoma cells towards B cell lymphoma development. The most striking results were observed after administration of anti-CD8 mAb: 90 to 100% of these treated mice developed Ly-1+ B cell lymphomas within 80 days. The effect of rIL-2 on dormant PLC was also tested. Administration of rIL-2 to 12-mo-old thymectomized mice terminated tumor dormancy in 94% of the treated mice within 66 days. Tests of the resulting B lymphomas for dual tropic recombinant virus/mink cell focus-inducing virus infection indicated that the breakdown of tumor dormancy did not result from development of pathogenic class I mink cell focus-inducing viruses. These results suggest that T cell subsets and/or their products are involved in the proliferation arrest of potential lymphoma cells present in thymectomized AKR mice.

Animals↗
PubMed1992

Antitumor effects of human recombinant interleukin-6 on acute myeloid leukemia in mice and in cell cultures.

Interleukin-6 (IL-6) has been shown to inhibit growth and induce differentiation of several myeloid leukemia cell lines. In this work, two in vivo models of acute myeloid leukemia (AML) in mice have been used to test the therapeutic potential of recombinant human IL-6. In mice inoculated by a transplantable AML tumor, IL-6 injections inhibited the development of leukemia and increased survival. The effect was related to dose and length of treatment. In a model of radiation-induced leukemogenesis in SJL/J mice, administration of low-dose IL-6 for 10 days, 4 months after irradiation, reduced the incidence of leukemia observed during 1 year, whereas granulocyte-macrophage colony-stimulating factor (GM-CSF) increased the incidence of leukemia. In vitro liquid cultures of leukemic blood cells obtained from AML patients showed that IL-6 slowed growth and decreased the proportion of blasts with an increase in more mature myeloid elements in 72% of M1, M2, M4 AML cases. In contrast, GM-CSF less often produced differentiation but stimulated leukemic cell growth in liquid cultures, without synergism by IL-6.

Animals↗
PubMed1992

Role of pineal melatonin and melatonin-induced-immuno-opioids in murine leukemogenesis.

The relationship between the pineal gland, melatonin and melatonin-induced-immuno-opioids with the response of C57Bl/6 mice to A-RadLV induced T cell lymphomas was investigated. Mice were injected at day 0 with A-RadLV and from day 10 they were treated chronically with melatonin 4 mg/kg body weight, naltrexone 1 mg/kg or phosphate buffered saline, throughout the experiment. In another protocol, groups of mice were a) surgical pinealectomized at day-14, b) functional pinealectomized (24:24 hours light) from day -20 and c) sham pinealectomized. At day 0 each group was inoculated intrathymically with A-RadLV. The results show that melatonin accelerated (p < 0.005) leukemogenesis whereas the surgical pinealectomy and the functional pinealectomy delayed it (p < 0.005 and p < 0.01). Moreover, the action of melatonin was blocked by naltrexone (p < 0.005), indicating the involvement of melatonin-induced-immuno-opioids in the development of the lymphomas.

Animals↗
PubMed1992

Absence of negative growth regulation in three new murine radiation-induced myeloid leukemia cell lines with deletion of chromosome 2.

Murine radiation-induced acute myeloid leukemia (RI-AML) may be considered as the experimental counterpart of human secondary leukemia. Three new myelomonocytic cell lines derived from RI-AML and carrying a partially deleted chromosome 2 are described. The RI-AML cells responded with increased proliferation after being incubated with the hemopoietic growth factors rG-CSF, rGM-CSF and IL-3. Increased proliferation of the same extent without any effect in differentiation, was also demonstrated in the RI-AML cells after incubation with IL-6 and with mouse lung conditioned medium (CM) and Krebs ascites tumor cells CM which induce differentiation in normal and most leukemic myeloid cells. Down-regulation of the c-myc gene and induction of (2'-5') oligo-adenylate synthetase (reflecting autocrine interferon secretion), two essential mechanisms operating during arrest of growth and concomitant differentiation, were demonstrated to be absent in RI-AML cells. In contrast, the M1 cells responded to the above differentiating factors with growth arrest and differentiation and with appropriate c-myc down-regulation and synthetase induction. The genetic basis for the distinct RI-AML cells' behavior may be connected with the loss or structural and/or functional abnormalities of DNA sequences located in the deleted part of chromosome 2 or in the respective allele. The presently described new RI-AML cell lines may be used for studies concerning myeloid leukemogenesis in general and secondary leukemia in particular.

2',5'-Oligoadenylate Synthetase↗
PubMed1992

Multiphase process involved in radiation induced murine AML.

Exposure of 3 month old SJL/J mice to a single dose of 300 r yielded 15-30% acute myelomonocytic leukemia (AML) development at a mean latency of 1 year. Additional treatment with dexamethasone shortly after irradiation increased leukemia incidence to 50%. All tumors were characterized by a partial deletion of one allele of chromosome 2 and the same deletion was detected in bone marrow and spleen cells of most irradiated mice, irrespective of the development of the disease. The presence of potential leukemic cells (PLC) in mice 4 months after the leukemogenic treatment was confirmed by transplantation studies. In these experiments PLC transition into overt AML seemed to be dependent on their transfer into irradiated recipients. Thus, exposure to 300 r results in the initiation of potential leukemic cells. Experiments were conducted in order to explore the possible role of radiation, cytokines and different hemopoietic growth factors on PLC promotion to overt leukemia. Exposure to 300 r, beside PLC initiation, was found to trigger the production of IL-6 and CSF-1; the additional administration of dexamethasone further increased CSF-1 levels. In vivo administration of CSF-1 into mice carrying radiation-induced PLC was most effective in PLC promotion to overt AML development.

Animals↗
PubMed1992

Initiation and promotion in radiation-induced myeloid leukemia.

Acute myelomonocytic leukemia develops in 10-30% of irradiated (300 rad) SJL/J mice, after a lag period of around one year. Additional treatment with dexamethasone shortly after irradiation increased leukemia incidence up to 50%. Experiments were conducted in order to demonstrate the existence of preleukemic cells in irradiated mice and to explore the possible role of dexamethasone, cyclophosphamide, and different hemopoietic growth factors on their promotion to overt leukemia. Transplantation of bone marrow cells from mice exposed to 300 rad plus dexamethasone into appropriate recipients, performed 4-5 months after leukemogenic treatment, resulted in acute myeloid leukemia (AML) development of donor origin in 70% of the recipients. Transfer of fractionated preleukemic bone marrow showed that the highest AML incidence developed in the recipients of fractions enriched in early hemopoietic precursors. The promoting effect of dexamethasone on preleukemic cells was confirmed by demonstrating its similar coleukemogenic effect whether administered within several hours or 130 days after radiation. Treatment with cyclophosphamide shortly after radiation could not replace the dexamethasone effect but was found to be complementary to the coleukemogenic effect of dexamethasone. Early administration of hemopoietic growth factors (starting 14 days after radiation and dexamethasone) showed that colony-stimulating factor (CSF) 1 increased the AML incidence (75%) and reduced its latency. Treatment with recombinant granulocyte-CSF (rG-CSF) had a reduced effect and recombinant granulocyte-macrophage CSF (rGM-CSF) had no promoting effect. However, administration of different factors several months after the leukemogenic treatment revealed that rGM-CSF increased AML incidence (75%) and shortened its latency, whereas rG-CSF and CSF-1 had no effect. In contrast, the late administration of recombinant interleukin 6 reduced AML incidence significantly (23%). The present results indicate that murine radiation induced AML is a multiphase process involving radiation induced preleukemia that can be promoted by different treatments.

Animals↗
PubMed1991

Prevention of spontaneous AKR T cell lymphomagenesis by 24-666, a virus isolated from an AKR B cell lymphoma.

Injection of a nonlymphomagenic ecotropic virus 24-666 isolated from a B cell lymphoma of AKR origin into young AKR mice (1-60 days old) inhibited spontaneous T cell lymphoma development. The reduction in T cell lymphoma incidence (16/106-15%) was accompanied with the appearance of B cell lymphomas (16/106-34%) in older mice (500 days mean latency). Infection of newborn to 60-day-old AKR mice with 24-666 prevented changes in thymus subpopulations and expression of MuLV-related cell surface antigens, normally observed in the thymus of 5- to 6-month-old AKR mice prior to lymphoma development. Thymuses of 24-666-infected 9- to 12-month-old mice lacked recombinant dual tropic virus (DTV) expression and retained the thymus pattern of 2-month-old AKR mice. At 12 months after 24-666 administration a striking decrease in Thy1.1 level and in the CD4+ CD8+ population and an increase in CD4- CD8- cells and in mu+ B cells, predominantly Ly1+, were observed. The presence of B cells in these thymuses was also reflected in the high response of thymocytes to LPS blastogenesis accompanied by a decreased response to PHA. Although T cell lymphoma development was markedly reduced by 24-666 administration, the establishment of potential lymphoma cells (PLC) was not affected. Transfer of lymphoid cells from 12-month-old grossly normal 24-666-infected mice to the appropriate recipients resulted in a high incidence (64-80%) of B cell lymphoma development. Thus, 24-666 seems to act through interference with the establishment of DTV in the thymus, thereby preventing PLC promotion to overt T cell lymphomas. Lack of the favorable microenvironment for PLC development in the T cell pathway enables PLC development in the B cell pathway in older mice.

Aging↗
PubMed1991

Prevention of spontaneous AKR T cell lymphomagenesis by elimination of potential lymphoma cells with antibody to specific gp 71 determinants.

AKR mice, highly susceptible to spontaneous T cell lymphomagenesis, were protected from developing the disease by a course of daily treatment with antibody 18-5 to gp 71 determinants (administered from birth to 10 days). Potential lymphoma cells (PLC) identified among bone marrow cells of untreated AKR mice since birth (using the transplantation bioassay method) were eliminated following treatment with antibody 18-5. Namely, transplantation of bone marrow cells and thymocytes of 250-day-old untreated AKR mice into (AKR/J x DBA/2)F1 and/or AKR recipients yielded 86-93% T cell lymphoma of AKR origin at a short mean latent period of 38-42 days. In contrast, transfer of lymphoid cells from 18-5-treated mice at a matching age caused only 7-13% T cell lymphoma of AKR origin. The accelerating effect of MCF 247 on lymphoma development in untreated AKR mice was not effective in 18-5-treated mice, probably due to lack of PLC that are promoted by MCF 247 to overt T cell lymphoma. The characteristic changes in thymus subpopulations preceding lymphoma development and coinciding with PLC identification in the thymus of untreated mice was prevented by 18-5. It is suggested that prevention of lymphoma development in AKR mice by passive antiviral immunotherapy involves elimination of PLC representing the initial tumorigenic phase in AKR lymphomagenesis.

Aging↗
PubMed1991

Validity of the in vitro system as a correlate of the in vivo model of RadLV lymphomagnesis.

Adult BL/6 mice are highly sensitive to lymphomagnesis by the radiation leukemia virus variant A-RadLV (80-100% T-cell lymphoma incidence after a latency of 70-110 days). This study shows that the in vivo elimination of T-cell subsets (including suppressor and cytotoxic T-cells) achieved by the repeated administration of cyclophosphamide, cyclosporin A, anti CD4 or anti CD8 mAb shortly after virus infection did not interfere with the lymphomagenic pathway. No reduction in the high lymphoma incidence or tumor latency was observed following the different treatments. Thus the suggestion on the basis of in vitro studies that the early phase of A-RadLV lymphomagenesis is associated with suppressor T-cells which abrogate a potential anti-tumor immune response has not been confirmed in these studies.

Animals↗
PubMed1990

Characteristics of potential lymphoma-inducing cells in mice sensitive or resistant to lymphomagenesis by radiation leukemia virus variants.

The relationship between the H-2-associated responsiveness of mice to radiation leukemia virus variants (A-RadLV and D-RadLV) lymphomagenesis and the characteristics of early occurring potential lymphoma-inducing cells (PLC) among thymus and bone marrow cells of these virus-infected mice was investigated. Sensitivity to virus-induced T-cell lymphomagenesis was shown to involve early occurrence of Thy-positive PLC, found predominantly among thymocytes, whereas resistance was rather related with early identification of PLC-Thy-negative cells mostly among bone marrow cells. PLC were further characterized in the sensitive (BL/6 + A-RadLV) and resistant (BL/6 + D-RadLV) situations by testing in parallel the tumorigenic potential (using the transplantation bioassay method) and type of thymus and bone marrow cell populations separated by different methods such as size fractionation by centrifugal elutriation, cytotoxic elimination of lymphocytes, or panning. The early occurring PLC among thymocytes of BL/6 mice 10-20 days following infection with A-RadLV were shown to be cortisone-resistant, Thy+, CD4+, and/or CD8+ medium size dividing thymocytes. PLC among thymocytes of BL/6 mice + D-RadLV, identified among the medium and large cell fractions, were shown to be cortisone-resistant Thy-, CD4-CD8- lymphocytes. High tumorigenic potential of PLC was demonstrated only among unseparated or separated (on size basis) bone marrow cells of BL/6 + D-RadLV (72-84%), whereas unseparated or separated fractions of bone marrow from BL/6 + A-RadLV had a low lymphomagenic potential (15-20%). The parallelism between the bone marrow fractions that induced optimal thymus cellularity following reconstitution of lethally irradiated mice and optimal lymphomagenicity stress the prothymocyte characteristics of PLC among bone marrow cells of BL/6 mice infected with D-RadLV. It is suggested that in resistant and sensitive haplotypes RadLV variants infect different cell populations and thereby induce PLC which differ in their capacity to present associative MuLV antigens with self H-2.

Animals↗
PubMed1979

Non-random duplication of chromosome 15 in murine T-cell leukemias induced in mice heterozygous for translocation T(14:15)6.

Trisomy of chromosome 15 is a highly regular feature of murine T-cell leukemogenesis. We have studied the chromosomal constitution of 7,12-dimethylbenza(a)anthracene (DMBA)-induced T-cell leukemias in C57BL X CBAT6T6 F1 mice. The CBAT6T6-derived chromosome T(14:15)6 was regularly duplicated whereas the C57BL-derived normal chromosome 15 was only present in one copy. It was concluded that the gene(s) that tend to duplicate in parallel with the neoplastic transformation of the prothymocyte to an overt leukemic cell have a greater chance of duplicating and/or may have a stronger promoting effect on leukemogenesis if stronger promoting effect on leukemogenesis if located on the CBA-derived, structurally rearranged T(14:15)6 than the corresponding genes located on the C57BL-derived normal chromosome 15.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1979

Effective tumor immunization induced by cells of elevated membrane-lipid microviscosity.

The immunogenicity of a series of mouse tumor lines propagated in vivo (T and B lymphomas and mammary adenocarcinoma) was tested after alteration of the cell membrane-lipid microviscosity. Tumor cells used for immunization were first treated to alter the lipid content, then irradiated and injected intraperitoneally into syngeneic mice. A second identical immunization was performed 14 days later. The degree of immunization in the treated mice was assessed by survival time after challenge with untreated viable tumor cells of the same origin as the immunizing cells. For all tumors tested, enrichment of the immunizing cells with cholesterol or cholesteryl hemisuccinate, which increased the membrane-lipid microviscosity significantly, afforded a marked increase in immunization, compared to that obtained with cells that were only irradiated. Furthermore, in over 90% of the mice that were pretreated with cholesteryl hemisuccinate-enriched cells, tumor growth after the challenge was not detectable. Because the lipid-modifying treatments of the immunizing cells involve no toxic substances, these results may provide the basis for a potent approach to immunotherapy of human cancer.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1978

Chromosome changes (trisomy 15) in murine T-cell leukemia induced by 1,12-dimethylbenz(a)anthracene (DMBA).

The banding pattern of DMBA-induced leukemias in C57BL/6 mice revealed a very constant chromosome pattern: the presence of trisomy 15 in almost all leukemic cells. This finding strongly suggests that chromosome 15 trisomy is the first detectable specific chromosome change associated with the development of DMBA-induced T-cell lymphomas. A similar association was previously shown with regard to development of radiation-leukemia-virus-induced T-cell lymphoma. It is conceivable that in tumors of diverse etiologies common cytogenetic changes may appear in the same common target-cell precursor, by a process of the "convergent microevolution" type.

9,10-Dimethyl-1,2-benzanthracene↗